1 CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Jiao Tong University School of Medicine and Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences (CAS), Chinese Academy of Sciences, Shanghai, People's Republic of China.
2 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences (CAS), Beijing, China.
Antioxid Redox Signal. 2019 Aug 10;31(5):369-386. doi: 10.1089/ars.2018.7688. Epub 2019 Apr 16.
Human embryonic stem cell derived-cardiovascular progenitor cells (hESC-CVPCs) are a promising cell source for cardiac repair, while the underlying mechanisms need to be elucidated. We recently observed cardioprotective effects of human pluripotent stem cell (hPSC)-CVPCs in infarcted nonhuman primates, but their effects on inflammation during early phase of myocardial infarction (MI) and the contribution of such effect to the cardioprotection are unclear. Injection of hESC-CVPCs into acutely infarcted myocardium significantly ameliorated the functional worsening and scar formation, concomitantly with reduced inflammatory reactions and cardiomyocyte apoptosis as well as increased vascularization. Moreover, hESC-CVPCs modulated cardiac macrophages toward a reparative phenotype in the infarcted hearts, and such modulation was further confirmed using human cardiovascular progenitor cell (hCVPC)-conditioned medium (hCVPC-CdM) and highly contained interleukin (IL)-4/IL-13. Furthermore, signal transducer and activator of transcription 6 (STAT6) was activated in hCVPC-CdM- and IL-4/IL-13-treated macrophages and in hESC-CVPC-implanted MI hearts, resulting in the polarization of macrophages toward a reparative phenotype in the post-MI hearts. However, hESC-CVPC-mediated modulation on macrophages and cardioprotection were abolished in STAT6-deficient MI mice. This is the first report about the immunoregulatory role played by hESC-CVPCs in the macrophage polarization in the infarcted hearts, its importance for the infarct repair, and the underlying signaling pathway. The findings provide new insight into the mechanism of microenvironmental regulation of stem cell-based therapy during acute MI. Implantion of hESC-CVPCs during the early phase of MI promotes infarct repair the modulation of macrophage polarization through secreted cytokine-mediated STAT6 activation. The findings suggest a therapeutic potential by modulating macrophage polarization during acute phase of MI.
人胚胎干细胞衍生的心血管祖细胞（hESC-CVPCs）是心脏修复的有前途的细胞来源，但其潜在机制尚需阐明。我们最近观察到人类多能干细胞（hPSC）-CVPCs 在非人类灵长类动物梗死中的心脏保护作用，但它们对心肌梗死（MI）早期炎症的影响以及这种作用对心脏保护的贡献尚不清楚。将 hESC-CVPCs 注射到急性梗死的心肌中可显著改善心脏功能恶化和瘢痕形成，同时减少炎症反应和心肌细胞凋亡，并增加血管生成。此外，hESC-CVPCs 可调节梗死心脏中的心脏巨噬细胞向修复表型，并且这种调节在使用人心血管祖细胞（hCVPC）条件培养基（hCVPC-CdM）和高含量白细胞介素（IL）-4/IL-13 时得到进一步证实。此外，信号转导和转录激活因子 6（STAT6）在 hCVPC-CdM 和 IL-4/IL-13 处理的巨噬细胞以及 hESC-CVPC 植入的 MI 心脏中被激活，导致巨噬细胞在 MI 后向修复表型极化。然而，在 STAT6 缺陷型 MI 小鼠中，hESC-CVPC 介导的巨噬细胞调节和心脏保护作用被消除。这是第一个关于 hESC-CVPCs 在梗死心脏中巨噬细胞极化的免疫调节作用、其对梗死修复的重要性以及潜在信号通路的报告。这些发现为急性 MI 期间基于干细胞的治疗的微环境调节机制提供了新的见解。在 MI 的早期阶段植入 hESC-CVPCs 通过细胞因子介导的 STAT6 激活调节巨噬细胞极化，促进梗死修复。这些发现提示通过在急性 MI 期间调节巨噬细胞极化具有治疗潜力。
